Poly(ethylene glycol) (PEG) derivatives activated with electrophilic groups are useful for coupling to amino groups of biologically active molecules, such as proteins. In particular, active esters of carboxylic acid derivatives of PEG have been used to attach PEG to proteins bearing amino groups.
U.S. Pat. No. 5,672,662 discloses PEG derivatives having a terminal propionic or butanoic acid moiety that can be used to prepare active esters suitable for conjugation to proteins or other molecules bearing amino groups. The synthetic method for propionic acid-substituted PEG described in the patent involves Michael addition of poly(ethylene glycol) to acrylonitrile followed by hydrolysis of the nitrile to form the carboxyl group. Hydrolysis of the nitrile requires severe reaction conditions, such as treatment with concentrated sulfuric acid at 95° C. or higher. The ether linkages in PEG are sensitive to such conditions and significant chain cleavage and reduction in yield can result from this process, particularly when relatively high molecular weight polymers are involved, such as polymers having a molecular weight above about 10,000 Da.
U.S. Pat. No. 5,523,479 to Sanders et al. discloses a method for forming ethercarboxylic acids by reacting an alcohol having a molecular weight of 32 to 6,000 Da with a tertiary alkyl ester of an α,β-unsaturated carboxylic acid in the presence of a catalyst, such as potassium hydroxide, followed by acid hydrolysis. The Sanders et al. patent does not address the use of higher molecular weight polymer reagents, such as PEG polymers having a molecular weight of about 10,000 Da or higher.
There is a need in the art for alternative methods for preparing propionic acid-terminated polymers, particularly high molecular weight polymers, in high yield without utilizing harsh reaction conditions that can cause chain cleavage within the polymer backbone (e.g., at the terminal methoxy group in the polymer backbone).